Estrogen and the central control of body fluid balance

Body fluid volume and electrolyte concentration are maintained at optimal levels by complex behavioral and physiological mechanisms that are integrated and coordinated by the central nervous system. From initial studies of estrogen effects on salt and water intake in the 1970s and later investigations of the role of estrogen in cardiovascular and neuroendocrine function, it has become increasingly clear that body fluid volume and osmotic regulation are affected by estrogen. In the early 1990s, estrogen receptors were identified throughout the central nervous system, in areas including circumventricular organs that detect humoral signals associated with body fluid challenges, and hypothalamic and hindbrain nuclei involved in behavioral, neuroendocrine, and cardiovascular responses to body fluid challenges. Taken together, the body of evidence amassed from more than 40 years of investigations suggests that the central actions of estrogen influence body fluid regulation and, more specifically, compensatory responses to perturbations of osmotic or volume balance in two interrelated ways. Estrogen alter the detection of signals by the central nervous system and, at the same time, act within central pathways to modify neurotransmitter systems that mediate specific responses to osmotic or volume challenges. This review focuses on the central actions of estrogen in influencing the cardiovascular, neuroendocrine, and behavioral processes that subserve body fluid regulation.     

Differential Control of the Sympathetic Nervous System by Leptin: Implications for Obesity

1. Leptin is a hormone that is secreted by adipocytes and delivered to the brain to regulate appetite and energy expenditure. Other effects of leptin include activation of the sympathetic nervous system and an increase in arterial pressure.2. Mounting evidence suggests that the sympathetic nervous system subserving different tissues is differentially controlled by leptin. For instance, leptin-induced regional increases in sympathetic nerve activity do not respond uniformly to baroreflex activation and hypothermia.3. In several mouse models of obesity, the ability of leptin to increase renal sympathetic nerve activity is preserved, despite resistance to leptin's effect on food intake, body weight and thermogenic sympathetic tone. Furthermore, obese mice also retain the increase in arterial pressure in response to leptin.3. Although they display a lack of metabolic responses to leptin, animal models of obesity preserve renal sympathetic and arterial pressure responses that potentially cause the adverse cardiovascular consequences of obesity. Thus, it is possible that excess leptin contributes to cardiovascular complications, even when a subject shows metabolic resistance to leptin.     

Human autonomic rhythms: vagal cardiac mechanisms in tetraplegic subjects.

1. We studied eight young men (age range: 20-37 years) with chronic, clinically complete high cervical spinal cord injuries and ten age-matched healthy men to determine how interruption of connections between the central nervous system and spinal sympathetic motoneurones affects autonomic cardiovascular control. 2. Baseline diastolic pressures and R-R intervals (heart periods) were similar in the two groups. Slopes of R-R interval responses to brief neck pressure changes were significantly lower in tetraplegic than in healthy subjects, but slopes of R-R interval responses to steady-state arterial pressure reductions and increases were comparable. Plasma noradrenaline levels did not change significantly during steady-state arterial pressure reductions in tetraplegic patients, but rose sharply in healthy subjects. The range of arterial pressure and R-R interval responses to vasoactive drugs (nitroprusside and phenylephrine) was significantly greater in tetraplegic than healthy subjects. 3. Resting R-R interval spectral power at respiratory and low frequencies was similar in the two groups. During infusions of vasoactive drugs, low-frequency R-R interval spectral power was directly proportional to arterial pressure in tetraplegic patients, but was unrelated to arterial pressure in healthy subjects. Vagolytic doses of atropine nearly abolished both low- and respiratory-frequency R-R interval spectral power in both groups. 4. Our conclusions are as follows. First, since tetraplegic patients have significant levels of low-frequency arterial pressure and R-R interval spectral power, human Mayer arterial pressure waves may result from mechanisms that do not involve stimulation of spinal sympathetic motoneurones by brainstem neurones. Second, since in tetraplegic patients, low-frequency R-R interval spectral power is proportional to arterial pressure, it is likely to be mediated by a baroreflex mechanism. Third, since low-frequency R-R interval rhythms were nearly abolished by atropine in both tetraplegic and healthy subjects, these rhythms reflect in an important way rhythmic firing of vagal cardiac motoneurones.     

Human investigations into the arterial and cardiopulmonary baroreflexes during exercise

After considerable debate and key experimental evidence, the importance of the arterial baroreflex in contributing to and maintaining the appropriate neural cardiovascular adjustments to exercise is now well accepted. Indeed, the arterial baroreflex resets during exercise in an intensity-dependent manner to continue to regulate blood pressure as effectively as at rest. Studies have indicated that the exercise resetting of the arterial baroreflex is mediated by both the feedforward mechanism of central command and the feedback mechanism associated with skeletal muscle afferents (the exercise pressor reflex). Another perhaps less appreciated neural mechanism involved in evoking and maintaining neural cardiovascular responses to exercise is the cardiopulmonary baroreflex. The limited information available regarding the cardiopulmonary baroreflex during exercise provides evidence for a role in mediating sympathetic nerve activity and blood pressure responses. In addition, recent investigations have demonstrated an interaction between cardiopulmonary baroreceptors and the arterial baroreflex during dynamic exercise, which contributes to the magnitude of exercise-induced increases in blood pressure as well as the resetting of the arterial baroreflex. Furthermore, neural inputs from the cardiopulmonary baroreceptors appear to play an important role in establishing the operating point of the arterial baroreflex. This symposium review highlights recent studies in these important areas indicating that the interactions of four neural mechanisms (central command, the exercise pressor reflex, the arterial baroreflex and cardiopulmonary baroreflex) are integral in mediating the neural cardiovascular adjustments to exercise.     

Angiotensin II in the brain and the autonomic control of the kidney

The kidney plays a central role in ensuring cardiovascular homeostasis, in that it functions to ensure that the variation in fluid intake is matched to that lost through normal everyday metabolism. The autonomic nervous system, via the renal sympathetic nerves, allows kidney function to be adjusted dynamically in response to changes in sensory information arising from the cardiovascular system, the soma, viscera and the higher cortical centres. At the level of the kidney, the sympathetic nerves innervate the vascular and tubular components, thereby regulating renal haemodynamics and fluid reabsorption. The processing of sensory information by the central nervous system involves nuclei associated with cardiovascular control and it is these nuclei which are influenced by angiotensin II generated locally in the brain. The angiotensin II appears to act in a neuromodulatory fashion or as a neurotransmitter. There is now sound evidence that the baroreflex control of sympathetic outflow to the kidney, at least, is under tonic inhibitory control by brain angiotensin II, which also facilitates the impact of the somatosensory system in mediating sympatho-excitation. The significance of brain angiotensin II in mediating reflex activation of the sympathetic nerves from other sensory systems has not yet been defined and needs to be resolved. Interestingly, it may be that deficits in the production of brain angiotensin II at these nuclei could contribute in part to the genesis of hypertension.     

Contrasting reflex influences of cardiac afferent nerves during coronary occlusion

Afferent neurons contained within cardiac sympathetic nerves may have important influences on the circulation when activated during myocardial ischemia. Although such activation is known to reflexly excite upper thoracic sympathetic efferent neurons, effects on other components of sympathetic outflow are unknown. Therefore, cardiac sympathetic afferent nerves were stimulated by occlusion of coronary arteries to investigate their reflex influences on renal sympathetic nerve activity and systemic arterial blood pressure. Responses were observed in anesthetized cats in which sympathetic and/or vagal cardiac afferent nerves remained intact and arterial baroreceptors remained intact or had been denervated. Stimulating sympathetic afferent neurons caused excitation of renal nerve activity, which was accompanied by variable changes in arterial pressure. Stimulation of vagal afferents by coronary occlusion consistently produced inhibition of renal nerve activity and marked depressor responses. When both components of cardiac innervation remained intact, increases or decreases in renal nerve activity and blood pressure were elicited by coronary artery occlusion in the presence or absence of arterial baroreceptors. These results illustrate that cardiac sympathetic afferent nerves can contribute significantly to cardiovascular control during myocardial ischemia.     

Osmotic thirst suppression in dogs exposed to low ambient temperature

Body temperature, urine output, osmotic and free water clearances, plasma osmolality, sodium and potassium concentrations, blood lactate level, osmotic thirst and central blood volume were measured in dogs exposed to cold (+1 to -8 degrees C) for 1-3 hours and compared to those obtained under control conditions at ambient temperatures (18-20 degrees C). In some additional experiments osmotic thirst threshold and arterial blood pressure during intravenous infusion of norepinephrine were also examined. Exposure to low ambient temperature caused an increase in the osmotic thirst threshold and rise in central blood volume. Transient increase in the urine output and free water clearance accompanied by a decrease in the urine osmolality were also observed. No changes were found in rectal temperature, plasma osmolality and plasma sodium concentration. Infusion of norepinephrine elevated the osmotic thirst threshold in a dose-dependent manner. It is concluded that the cold-induced suppression of osmotic thirst may result from the increased central blood volume. A possible involvement of the sympathetic nervous system in the thirst inhibition in low ambient temperature is also considered.     

Differential control of efferent sympathetic activity revisited

This article reviews 40 years of research (1970–2010) into the capability of the efferent sympathetic nervous system to display differential responsiveness. Discovered first were antagonistic changes of activity in sympathetic filaments innervating functionally different sections of the cardiovascular system in response to thermal stimulation. During the subsequent four decades of investigation, a multitude of differential sympathetic efferent response patterns were identified, ranging from opposing activity changes at the level of multi-fiber filaments innervating different organs to the level of single fibers controlling functionally different structures in the same organ. Differential sympathetic responsiveness was shown to be displayed in response to exogenous or artificial stimulation of afferent sensory fibers transmitting particular exogenous stimuli, especially those activating peripheral nociceptors. Moreover, sympathetic differentiation was found to be characteristic of autonomic responses to environmental changes by which homeostasis in the broadest sense would be challenged. Heat or cold loads or their experimental equivalents, altered composition of inspired air or changes in blood gas composition, imbalances of body fluid control, and exposure to agents challenging the immune system were shown to elicit differential efferent sympathetic response patterns which often displayed a high degree of specificity. In summary, autonomic adjustments to changes of biometeorological parameters may be considered as representative of the capability of the sympathetic nervous system to exert highly specific efferent control of organ functions by which bodily homeostasis is maintained.     

Central command: control of cardiac sympathetic and vagal efferent nerve activity and the arterial baroreflex during spontaneous motor behaviour in animals

Feedforward control by higher brain centres (termed central command) plays a role in the autonomic regulation of the cardiovascular system during exercise. Over the past 20 years, workers in our laboratory have used the precollicular-premammillary decerebrate animal model to identify the neural circuitry involved in the CNS control of cardiac autonomic outflow and arterial baroreflex function. Contrary to the traditional idea that vagal withdrawal at the onset of exercise causes the increase in heart rate, central command did not decrease cardiac vagal efferent nerve activity but did allow cardiac sympathetic efferent nerve activity to produce cardiac acceleration. In addition, central command-evoked inhibition of the aortic baroreceptor-heart rate reflex blunted the baroreflex-mediated bradycardia elicited by aortic nerve stimulation, further increasing the heart rate at the onset of exercise. Spontaneous motor activity and associated cardiovascular responses disappeared in animals decerebrated at the midcollicular level. These findings indicate that the brain region including the caudal diencephalon and extending to the rostral mesencephalon may play a role in generating central command. Bicuculline microinjected into the midbrain ventral tegmental area of decerebrate rats produced a long-lasting repetitive activation of renal sympathetic nerve activity that was synchronized with the motor nerve discharge. When lidocaine was microinjected into the ventral tegmental area, the spontaneous motor activity and associated cardiovascular responses ceased. From these findings, we conclude that cerebral cortical outputs trigger activation of neural circuits within the caudal brain, including the ventral tegmental area, which causes central command to augment cardiac sympathetic outflow at the onset of exercise in decerebrate animal models.     

Role of differential changes in sympathetic nerve activity in the preparatory adjustments of cardiovascular functions during freezing behaviour in rats

Freezing behaviour is associated with a distinct pattern of changes in cardiovascular function, which has been considered as a preparatory reflex for 'fight or flight' behaviour. However, the detailed mechanisms underlying preparatory cardiovascular adjustments and their physiological implications have received less attention. We studied responses in renal and lumbar sympathetic nerve activity and cardiovascular function during freezing behaviour in conscious rats, which was induced by exposure to loud white noise. Freezing behaviour was associated with regionally specific alterations in sympathetic nerve activity, in that renal sympathetic nerve activity increased while lumbar sympathetic nerve activity did not change. Moreover, freezing behaviour was associated with differential shifts in baroreflex control of sympathetic outflows, which could help to explain the selective responses in renal and lumbar sympathetic nerve activity during freezing behaviour. These differential changes in sympathetic outflows would result in a visceral vasoconstriction without having any impact on the skeletal muscle vasculature. These cardiovascular adjustments during freezing behaviour may help to explain the immediate and massive increase in muscular blood flow that occurs at the onset of fight or flight behaviour. It is hypothesized that central command originating from the defence area could somehow modulate separate baroreflex pathways, causing differential changes in sympathetic nerve activity to generate the preparatory cardiovascular adjustments during the freezing behaviour.     

Sympathetic transients caused by abrupt alterations of carotid baroreceptor activity in humans

We examined the role of carotid baroreceptors in the short-term modulation of sympathetic outflow to the muscle vascular bed and parasympathetic outflow to the heart in 10 healthy adults. Afferent carotid baroreceptor activity was modified with 30-mmHg neck suction or pressure applied during held expiration, and efferent sympathetic activity was measured with microelectrodes inserted percutaneously into peroneal nerve muscle fascicles. Sympathetic responses were conditioned importantly by directional changes of carotid transmural pressure: increased pressure (onset of neck suction or offset of neck pressure) inhibited (totally) sympathetic activity, and reduced pressure (offset of neck suction or onset of neck pressure) augmented sympathetic activity. Responses occurred after a latency of about 2 s and did not persist as long as changes of neck-chamber pressure. Cardiac intervals were prolonged by increased carotid transmural pressures and shortened by decreased carotid transmural pressures, but, in contrast to sympathetic responses, cardiac responses adapted only slightly during neck-chamber pressure changes. Our results suggest that in the human a common baroreceptor input is processed differently in central vagal and sympathetic networks. Muscle sympathetic responses to changing levels of afferent baroreceptor traffic are profound but transitory. They appear to be conditioned more by changes of arterial pressure than by its absolute levels.     

The bed nucleus of the stria terminalis modulates exercise-evoked cardiovascular responses in rats

Dynamic exercise evokes sustained cardiovascular changes, which are characterized by blood pressure and heart rate (HR) increases. Although it is well accepted that there is a central nervous system (CNS) mediation of cardiovascular adjustments during dynamic exercise, information on the role of specific CNS structures is limited. The bed nucleus of the stria terminalis (BST) is a forebrain structure known to be involved in central cardiovascular control. Based on this, we tested the hypothesis that BST modulates HR and mean arterial pressure (MAP) responses evoked when rats are submitted to dynamic exercise. Male Wistar rats were tested at three levels of exercise (0.4, 0.8 and 1 km h⁻¹) on a rodent treadmill before and after BST treatment with CoCl₂, a non-selective neurotransmission blocker. Bilateral microinjection of CoCl₂ (1 nmol in 100 nl artificial cerebrospinal fluid) into the BST reduced the pressor response to exercise at 0.4 km h⁻¹ as well as the tachycardic responses evoked by exercise at 0.4, 0.8 and 1 km h⁻¹. The BST treatment with CoCl₂ did not affect baseline MAP or HR, suggesting a lack of tonic BST influence on cardiovascular parameters at rest. Moreover, BST treatment with CoCl₂ did not affect motor performance in the open-field test, which indicates that effects of BST inhibition on cardiovascular responses to dynamic exercise are not due to changes in motor activity. The present results suggest that local neurotransmission in the BST modulates exercise-related cardiovascular adjustments. Data indicate that BST facilitates pressor and tachycardic responses evoked by dynamic exercise in rats.     

The melanocortin system is involved in regulating autonomic nerve activity through central pituitary adenylate cyclase-activating polypeptide

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a peptidergic neurotransmitter that is highly expressed in the nervous system. We have previously reported that a central injection of PACAP leads to changes in the autonomic nervous system tones including sympathetic excitation and parasympathetic inhibition. An anatomical study revealed that melanocortin and PACAP are colocalized in some hypothalamic nuclei. Here, we investigated the possible role of the melanocortin system in autonomic control by PACAP using SHU9119, an antagonist of the melanocortin receptors (MC3-R/MC4-R). Pretreatment with SHU-9119 did not affect the activating neural responses of adrenal, renal, and lumbar sympathetic nerves following a PACAP injection However, SHU9119 significantly eliminated the suppressing effect of a PACAP injection on gastric vagal nerve activity and excitation effects on liver and brown adipose tissue sympathetic nerve activities. These results suggest that the brain melanocortin system might play a key role in the control of thermogenic sympathetic outflows and digestive parasympathetic outflow by PACAP, but this system does not participate in the central effects of PACAP on cardiovascular function and neural activities of renal, adrenal, and lumbar sympathetic nerves.     

Calcitonin gene-related peptide antagonism attenuates the haemodynamic and glycaemic responses to acute hypoxaemia in the late gestation sheep fetus

The fetal defence to acute hypoxaemia involves cardiovascular and metabolic responses, which include peripheral vasoconstriction and hyperglycaemia. Both these responses are mediated via neuroendocrine mechanisms, which require the stimulation of the sympathetic nervous system. In the adult, accumulating evidence supports a role for calcitonin gene-related peptide (CGRP) in the activation of sympathetic outflow. However, the role of CGRP in stimulated cardiovascular and metabolic functions before birth is completely unknown. This study tested the hypothesis that CGRP plays a role in the fetal cardiovascular and metabolic defence responses to acute hypoxaemia by affecting sympathetic outflow. Under anaesthesia, five sheep fetuses at 0.8 of gestation were surgically instrumented with catheters and a femoral arterial Transonic flow-probe. Five days later, fetuses were subjected to 0.5 h hypoxaemia during either i.v. saline or a selective CGRP antagonist in randomised order. Treatment started 30 min before hypoxaemia and ran continuously until the end of the challenge. Arterial samples were taken for blood gases, metabolic status and hormone analyses. CGRP antagonism did not alter basal arterial blood gas, metabolic, cardiovascular or endocrine status. During hypoxaemia, similar falls in P _a,O2 occurred in all fetuses. During saline infusion, hypoxaemia induced hypertension, bradycardia, femoral vasoconstriction, hyperglycaemia and an increase in haemoglobin, catecholamines and neuropeptide Y (NPY). In contrast, CGRP antagonism markedly diminished the femoral vasoconstrictor and glycaemic responses to hypoxaemia, and attenuated the increases in haemoglobin, catecholamines and NPY. Combined, these results strongly support the hypothesis that CGRP plays a role in the fetal cardiovascular and metabolic defence to hypoxaemia by affecting sympathetic outflow.     

Exposure to a hot environment can activate rostral ventrolateral medulla-projecting neurones in the hypothalamic paraventricular nucleus in conscious rats

A major integrative site within the brain for autonomic function is the hypothalamic paraventricular nucleus (PVN). Several studies have suggested that the PVN may be involved in the responses regulating body temperature. Hyperthermia elicits redirection of blood flow from the viscera to the periphery and involves changes in sympathetic nerve activity mediated by the central nervous system. The hypothalamic PVN includes neurones that project to the rostral ventrolateral medulla (RVLM), an important autonomic region involved in the tonic regulation of sympathetic nerve activity. This pathway could contribute to the cardiovascular changes induced by hyperthermia. The PVN has a high concentration of nitrergic neurones and it is known that nitric oxide within the brain mediates heat dissipation. Thus the aims of this study were to determine whether RVLM-projecting neurones in the PVN are activated by heat and whether those neurones are also nitrergic. The results show that, compared with control conditions, exposure of conscious rats to a hot environment of 39 degrees C significantly increased the number of neurones containing a Fos-positive nucleus (a marker of activation) and significantly increased the number of activated RVLM-projecting neurones in the PVN. Also, although heating significantly increased the number of activated nitrergic PVN neurones, triple-labelled neurones (i.e. activated, nitrergic and RVLM projecting) in the PVN were rarely observed. The results suggest that RVLM-projecting neurones in the PVN may play a role in responses to heat exposure but these are not nitrergic.     

Differential effects of behaviour on sympathetic outflow during sleep and exercise

The responses of renal and lumbar sympathetic outflow to changes in behavioural states were reviewed in this paper. During rapid eye movement (REM) sleep, renal sympathetic nerve activity was decreased while lumbar sympathetic nerve activity increased. These diverse changes in sympathetic nerve activity observed during REM sleep help explain the responses in regional blood flow to REM sleep; that is renal blood flow increased while muscle blood flow decreased. By contrast, exercise increased both renal and muscle sympathetic nerve activity. The degree of physical activity was correlated with the magnitude of the increases in renal and muscle sympathetic nerve activity. There was a significant (P<0.05) linear relationship between renal sympathetic nerve activity and systemic arterial pressure over the transition between non-rapid eye movement (NREM) sleep, quiet awake, moving and grooming states in the rats. This suggests that sympathetic outflows seem to be modulated quantitatively to meet cardiovascular demand caused by changes in the level of physical activity. It is therefore concluded that sympathetic outflow seems to be regulated in a state-specific manner during sleep and exercise.     

Pathomorphologic changes in the sympathetic portion of the autonomic nervous system and cardiovascular pathology]

Neurohistochemical and ultrastructural study of the sympathetic innervation of the cardiovascular system indicated its important role in the age alterations and genesis of certain diseases. Early beginning (from the age of 30) of the involution of the heart adrenergic plexus is confirmed in healthy persons. Focal desympathization of the myocardium is detected in sudden cardiac death. A decrease of sympathetic plexus density in zones undergoing atherosclerotic changes is of importance in the genesis of atherosclerosis. In arterial hypertension a primary stage of sympathetic neurones hypertrophy is changed into the phase of the mediators exhaustion in the sympathetic plexus. Myocardiopathies are characterized by progressing myocardial desympathization. An important problem of cardiosurgery is methods of heart reinnervation at its transplantation.     

Numerical simulation of the effect of sodium profile on cardiovascular response to hemodialysis

PURPOSE: We developed a numerical model that predicts cardiovascular system response to hemodialysis, focusing on the effect of sodium profile during treatment. MATERIALS AND METHODS: The model consists of a 2-compartment solute kinetics model, 3-compartment body fluid model, and 12-lumped-parameter representation of the cardiovascular circulation model connected to set-point models of the arterial baroreflexes. The solute kinetics model includes the dynamics of solutes in the intracellular and extracellular pools and a fluid balance model for the intracellular, interstitial, and plasma volumes. Perturbation due to hemodialysis treatment induces a pressure change in the blood vessels and the arterial baroreceptors then trigger control mechanisms (autoregulation system). These in turn alter heart rate, systemic arterial resistance, and cardiac contractility. The model parameters are based largely on the reported values. RESULTS: We present the results obtained by numerical simulations of cardiovascular response during hemodialysis with 3 different dialysate sodium concentration profiles. In each case, dialysate sodium concentration profile was first calculated using an inverse algorithm according to plasma sodium concentration profiles, and then the percentage changes in each compartment pressure, heart rate, and systolic ventricular compliance and systemic arterial resistance during hemodialysis were determined. A plasma concentration with an upward convex curve profile produced a cardiovascular response more stable than linear or downward convex curves. CONCLUSION: By conducting numerical tests of dialysis/cardiovascular models for various treatment profiles and creating a database from the results, it should be possible to estimate an optimal sodium profile for each patient.     

Identification of Sites of Sympathetic Outflow During Concurrent Recordings of Sympathetic Nerve Activity and fMRI

The sympathetic division of the nervous system is critical for maintaining both resting arterial pressure and for producing changes in regional perfusion required by behavioral state changes. A primary determinant of arterial pressure is the level of vasoconstriction within skeletal muscle. It is well established that there is a tight relationship between dynamic changes in arterial pressure and muscle sympathetic nerve activity (MSNA) through the workings of the baroreflex. While the central circuitry underlying the baroreflex has been extensively investigated in anesthetized experimental animals, few studies have investigated the central circuitry responsible for the baroreflex in awake human subjects. Recently we were the first to record concurrently MSNA (using microneurography) and brain activity (using functional magnetic resonance imaging) in awake humans in a series of experiments designed to determine the central circuitry underlying the baroreflex in humans. We confirmed that the baroreflex involves activity changes within the nucleus tractus solitarius, caudal ventrolateral, and rostral ventrolateral medulla. Because conditions such as essential hypertension, obesity, and obstructive sleep apnea are all characterized by significant increases in resting MSNA, it is important to understand both brainstem and cortical sites involved in regulating resting levels of MSNA. Future investigations which define cortical sites involved in generating and modulating MSNA are important if we are to understand the underlying mechanisms of many conditions characterized by hypertension. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.     

Melatonin modulates the light-induced sympathoexcitation and vagal suppression with participation of the suprachiasmatic nucleus in mice

In mammals, the autonomic nervous system mediates the central circadian clock oscillation from the suprachiasmatic nucleus (SCN) to the peripheral organs, and controls cardiovascular, respiratory and gastrointestinal functions. The present study was conducted in mice to address whether light signals conveyed to the SCN can control peripheral autonomic functions, and further examined the impact of centrally administered melatonin on peripheral autonomic functions via activation of melatonin receptor signalling. In vivo electrophysiological techniques were performed in anaesthetised, open-chest and artificially ventilated mice whilst monitoring the arterial blood pressure and heart rate. Light induced an increase of the renal sympathetic nerve activity, arterial blood pressure and heart rate immediately after lights on. Conversely, light rapidly suppressed the gastric vagal parasympathetic nerve activity, which was affected neither by hepatic vagotomy nor by total subdiaphragmatic vagotomy. These autonomic responses were mediated by the SCN since bilateral SCN lesion totally abolished the light-evoked neuronal and cardiovascular responses. Melatonin administered intracerebroventricularly ( i.c.v .) attenuated the sympathetic and vagal nerve activities in a dose-dependent manner with a threshold of 0.1 ng and these effects were blocked by i.c.v . pre-treatment of the competitive melatonin receptor antagonist luzindole. These results suggest that light induces sympathoexcitation and vagal suppression through the SCN and that melatonin modulates the light-induced autonomic responses via activation of the central melatonin receptor signalling.